Method of treating conditions related to the PGI2 receptor

Abstract

Provided in some embodiments are titration packages, kits, and methods of treating pulmonary arterial hypertension comprising prescribing and/or administering to a patient in need thereof 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof, via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, over a period of no more than about nine weeks until an optimized dose is administered.

What is claimed is: 
     
       1. A method for the treatment of pulmonary arterial hypertension (PAH) in a patient, the method comprising orally administering to the patient a pharmaceutical composition comprising an amount of 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof,
 wherein the amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, for treatment of PAH in the patient is determined by using a titration scheme comprising: one or more cycles of escalating the dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, that is administered, one or more cycles of de-escalating the dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, that is administered, or both, and 
 wherein the titration scheme is initiated at an initial dose equivalent to 0.05 mg of Compound 1 once daily. 
 
     
     
       2. A method for the treatment of pulmonary arterial hypertension (PAH) in a patient, the method comprising orally administering to the patient a pharmaceutical composition comprising an amount of 2-(((1r,4r)-4-(((4-chlorophenyl)(phenyl)carbamoyloxy)methyl)cyclohexyl)methoxy)acetic acid (Compound 1), or a pharmaceutically acceptable salt, hydrate, or solvate thereof,
 wherein Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is administered via a titration scheme that comprises the up-titration of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and 
 wherein the titration scheme comprises: 
 (i) administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at an initial dose equivalent to 0.05 mg of Compound 1 once daily for about one week; and 
 provided that the patient tolerates the initial dose, administering an increased dose that is equivalent to 0.1 mg of Compound 1 once daily; or provided that the patient does not tolerate the initial dose, administering a decreased dose; 
 or (ii) administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at an initial dose equivalent to 0.01 mg of Compound 1 twice daily for about one week; and 
 provided that the patient tolerates the initial administered dose, administering an increased dose that is equivalent to 0.02 mg of Compound 1 twice daily; or provided that the patient does not tolerate the initial administered dose, administering a decreased dose. 
 
     
     
       3. The method of  claim 1 , wherein the composition is in the form of a tablet. 
     
     
       4. The method of  claim 1 , wherein the composition is in the form of a capsule. 
     
     
       5. The method of  claim 1 , wherein the titration scheme comprises cycles of dose adjustments at intervals of about a week. 
     
     
       6. The method of  claim 5 , wherein:
 if the patient tolerates the initial administered dose equivalent to 0.05 mg of Compound 1 once daily then the administered dose is increased to a dose that is equivalent to 0.1 mg of Compound 1 once daily; 
 or if the patient does not tolerate the initial administered dose equivalent to 0.05 mg of Compound 1 once daily, then the administered dose is decreased for a cycle and optionally increased thereafter. 
 
     
     
       7. The method of  claim 6 , wherein:
 if the patient tolerates the administered dose equivalent to 0.1 mg of Compound 1 once daily then the administered dose is increased to a dose that is equivalent to 0.2 mg of Compound 1 once daily; 
 or if the patient does not tolerate the administered dose equivalent to 0.1 mg of Compound 1 once daily, then the administered dose is decreased for a cycle and optionally increased thereafter. 
 
     
     
       8. The method of  claim 7 , wherein:
 if the patient tolerates the administered dose equivalent to 0.2 mg of Compound 1 once daily then the administered dose is increased to a dose that is equivalent to 0.3 mg of Compound 1 once daily; 
 or if the patient does not tolerate the administered dose equivalent to 0.2 mg of Compound 1 once daily, then the administered dose is decreased for a cycle and optionally increased thereafter. 
 
     
     
       9. The method of  claim 8 , wherein:
 if the patient tolerates the administered dose equivalent to 0.3 mg of Compound 1 once daily then the administered dose is increased to a dose that is equivalent to 0.4 mg of Compound 1 once daily; 
 or if the patient does not tolerate the administered dose equivalent to 0.3 mg of Compound 1 once daily, then the administered dose is decreased for a cycle and optionally increased thereafter. 
 
     
     
       10. The method of  claim 1 , wherein the titration scheme comprises cycles of dose adjustments at intervals of about 5 days. 
     
     
       11. The method of  claim 1 , wherein the titration scheme comprises cycles of dose escalations, dose de-escalations, or both, of the amount of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof that is administered, wherein the cycles are repeated until an optimized dose is administered, and wherein each cycle lasts about a week. 
     
     
       12. The method of  claim 1 , wherein the method comprises administering a daily dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.03 mg, 0.04 mg, 0.06 mg, or 0.08 mg of Compound 1. 
     
     
       13. The method of  claim 1 , wherein the method comprises administering a daily dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.1 mg of Compound 1. 
     
     
       14. The method of  claim 1 , wherein the method comprises administering a daily dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.2 mg of Compound 1. 
     
     
       15. The method of  claim 1 , wherein the method comprises administering a daily dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.3 mg of Compound 1. 
     
     
       16. The method of  claim 1 , wherein the method comprises administering a daily dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.4 mg of Compound 1. 
     
     
       17. The method of  claim 1 , wherein the method comprises administering a daily dose of Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, equivalent to 0.6 mg of Compound 1. 
     
     
       18. The method of  claim 1 , wherein the Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is Compound 1, or a hydrate or solvate thereof. 
     
     
       19. The method of  claim 1 , wherein the Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, is Compound 1. 
     
     
       20. The method of  claim 1 , wherein the pulmonary arterial hypertension (PAH) is selected from:
 idiopathic PAH; 
 familial PAH; 
 PAH associated with a collagen vascular disease selected from: scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, Takayasu's arteritis, polymyositis, and dermatomyositis; 
 PAH associated with a congenital heart disease selected from: atrial septic defect (ASD), ventricular septic defect (VSD) and patent ductus arteriosus in a patient; 
 PAH associated with portal hypertension; 
 PAH associated with HIV infection; 
 PAH associated with ingestion of a drug or toxin; 
 PAH associated with hereditary hemorrhagic telangiectasia; 
 PAH associated with splenectomy; 
 PAH associated with significant venous or capillary involvement; 
 PAH associated with pulmonary veno-occlusive disease (PVOD); and 
 PAH associated with pulmonary capillary hemangiomatosis (PCH) in a patient. 
 
     
     
       21. The method of  claim 1 , wherein the dose is escalated by an increment equivalent to about 0.05 mg of Compound 1 per cycle. 
     
     
       22. The method of  claim 2 , wherein the titration scheme comprises:
 (i) administering Compound 1, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, at an initial dose equivalent to 0.05 mg of Compound 1 once daily for about one week; and 
 provided that the patient tolerates the initial dose, administering an increased dose that is equivalent to 0.1 mg of Compound 1 once daily; or provided that the patient does not tolerate the initial dose, administering a decreased dose. 
 
     
     
       23. The method of  claim 2 , wherein the increased dose equivalent to 0.1 mg of Compound 1 once daily is administered for about a week.